Genetic associations between rheumatoid arthritis and specific HLA class II genes provide clues to understanding the molecular basis for disease susceptibility. There is a remarkable structural relationship among different RA susceptibility genes, in which each of the associated class II alleles encodes a sequence of key amino acids termed the "shared epitope." In this proposal, we outline mechanistic models to account for the shared epitope association with RA, and interpret these models in the context of an HLA-directed pathway for the development of disease. We propose to test specific hypotheses developed from these alternative models, through a series of aims which will characterize the structural basis for TCR recognition of the shared epitope region, identify altered T cell activation resulting from recognition of shared epitope, and investigate and test mechanisms by which the shared epitope may be involved in the generation or modulation of self-recognition during antigen presentation and processing. We propose that the shared epitope association with RA is not solely based on a specific peptide binding motif and peptide determinant selection, but rather is influenced by a strongly biased direct recognition of shared epitope residues by direct T cell contact. The implications for T cell development, selection, and activation will be tested using a combination of human T cell clones and murine transgenic animal models.